The present invention is enclosed within the pharmaceutical research and industry field. In particular, it is centred on the identification of previously described or new chemical compounds useful in the treatment of any pathology related to the phosphorylating activity of the enzyme GSK-3 as, for instance, Alzheimer""s Disease, AD.
The progressive ageing of the world population brings on the undesired consequence of an increase in the incidence of senile dementia, The most widely spread of this dementia is AD, which affects near 50% of the population aged 85 years or more and, as longevity increases, this rate will also increase unless the strategies to prevent or arrest the neurocdegenerative processes become successful.
There are several biochemical processes affected in AD patients. The treatment of these pathologies would be a correct approach to diminish the damage caused by the disease but, up to now, the only drugs commercialised are some agents that improve cholinergic neurotransmission. Although temporarily, they alleviate the cognoscitive and memory failures associated to AD, At present, most of the research is mainly focused on the search of new agents useful in the treatment of two other pathologies, senile plaques and neurofibrillary tangles, which constitute the major histological lesions observed in AD brains and are also associated with the cholinergic neurotransmission [xe2x80x9cModulation of xcex2-amyloid precursor protein processing and tau phosphorylation by acetylcholine receptorsxe2x80x9d Hellstrxc3x6m-Lindahl, E.; Eur. J. Pharmacology 2000, 393, 255-2633].
The object of this invention is precisely related to the discovery of new products which are able to interfere the developing of neurofibrillary tangles. These tangles are formed by paired helical filaments whose main component is an intracellular, polar, quite hydrosoluble, microtubule-associated phosphoprotein protein named tau which appears abnormally phosphorylated. In normal cells, tau is essential for the integrity and stability of the neuronal cytoskeleton but its biological activity appears regulated by the degree of phosphorylation: normal brain tau contains 2-3 moles phosphate/mole protein while AD abnormally hyperphosphorylated tau contains 5-9 moles phosphate/mole protein [xe2x80x9cBrain microtubule associated proteins: Modifications and diseasexe2x80x9d (Kosic, K. and Avila, J. Eds.) Chap. 7: xe2x80x9cTau phosphatasesxe2x80x9d Iqbal, K. et al. Harwood Academic Publishers, New York, pp. 95-111 (1997)]. Pathological tau presents a diminished capacity to stabilise microtubules, bringing on the corresponding neuronal degeneration, and aggregates into the filaments that form the tangles.
Hyperphosphorylation of tau and progress of AD relation is well demonstrated. Thus, selective inhibitors of the enzymes (kinases) that catalyse the abnormal phosphorylation of tau could become very useful therapeutic agents in the treatment of AD. In fact, the search for these inhibitors is an outstanding field of current pharmaceutical research [xe2x80x9cTau protein as a therapeutic target in Alzheimer""s disease and other neurodegenerative diseasesxe2x80x9d Larner, A. J.; Expert Opinion on Therapeutic Patents 1999, 9, 1359-1370].
Neither the whole tau hyperphosphorylation process nor all the kinases involved in it are completely known, but it is clear that GSK-3 is an in vivo kinase in brain and that it plays a central role in the pathological process. The discovery of non-toxic GSK-3 inhibitors would be very important, both from the scientific and industrial points of view, because, until now, the lithium cation is the only agent that have proved to inhibit GSK-3 but in therapeutically unacceptable high concentrations. A comprehensive review on this subject may be found in xe2x80x9cInhibition of tau phosphorylation: a new therapeutic strategy for the treatment of Alzheimer""s disease and other neurodegenerative disordersxe2x80x9d Castro, A.; Martinez, A.; Expert Opinion on Therapeutic Patents 2000, 10, 1519-1527. It has also been observed that insulin inactivates GSK-3 and that non-dependent insulin diabetes mellitus is related to the activation of the enzyme, so, there is the possibility that GSK-3 inhibitors could became new useful agents in the treatment of that kind of diabetes.
Research conducted by the present applicants has recently shown that a new family of aromatic and heteroaromatic ketones exhibit GSK-3 inhibitor activity at a micromolar or lower concentration level, thus leading to the completion of the present invention.
In a first aspect, the present invention provides compounds of general formula I: 
wherein:
X represents xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CRxe2x80x94, xe2x80x94CRxe2x95x90CRxe2x80x94, xe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NRxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94CRxe2x95x90Nxe2x80x94, xe2x80x94CHxe2x95x90N(O)xe2x80x94, xe2x80x94CRxe2x95x90N(O)xe2x80x94 or any other atom or group of atoms capable of forming a 5- or 6-membered heterocyclic ring;
Y1, Y2 and Y3 independently represent hydrogen or halogen;
R1, R2 and R3 are independently represent hydrogen, halogen, hydrocarbyl (xe2x80x94R), hydroxyl (xe2x80x94OH), hydrocarbyloxy (xe2x80x94Oxe2x80x94R), mercapto (xe2x80x94SH), hydrocarbylthio (xe2x80x94Sxe2x80x94R), hydrocarbylsulfinyl (xe2x80x94SOxe2x80x94R), hydrocarbylsulfonyl (xe2x80x94SO2xe2x80x94R), nitro (xe2x80x94NO2), amino (xe2x80x94NH2), hydrocarbylamino (xe2x80x94NHR), bis(hydrocarbyl)amino (xe2x80x94NR2), hydrocarbylcarbonylamino (xe2x80x94NHxe2x80x94COxe2x80x94R), cyano (xe2x80x94CN), carbamoyl (xe2x80x94CONH2), hydrocarbylcarbamoyl (xe2x80x94CONHR), bis(hydrocarbyl)carbamoyl (xe2x80x94CONR2), carboxyl (xe2x80x94CO2H), hydrocarbyloxycarbonyl (xe2x80x94CO2R), formyl (xe2x80x94CHO), hydrocarbylcarbonyl (xe2x80x94COR), hydrocarbylcarbonyloxy (xe2x80x94OCOR), optionally substituted heteroaryl or optionally substituted heterocyclic;
the hydrocarbyl group R is a straight or branched chain hydrocarbyl group selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl and aralkynyl, which may optionally be substituted by one or more substituents, selected from those defined above in relation to R1, R2 and R3.
As described below, the compounds of formula (I) are inhibitors of kinases in general and of GSK-3 in particular, and are therefore useful as possible therapeutic agents.
Therefore, in a second aspect, the invention provides the use of a compound of formula (I) as a medicament, in particular in the manufacture of a medicament for the treatment including prophylaxis of diseases mediated by the activation of GSK-3.
In a third aspect, the invention provides a method of treating a mammal, notably a human, affected by a disease mediated by the activation of GSK-3, which comprises administering to the affected individual a therapeutically effective amount of a compound of formula (I), or a pharmaceutical composition thereof.
In further aspects, the present invention provides a pharmaceutical preparation which contain as active ingredient a compound or compounds of the invention, as well as a process for the preparation of such a pharmaceutical.
In the compounds of formula (I), the hydrocarbyl group R and the hydrocarbyl component of the other groups is a straight or branched chain hydrocarbyl group selected from alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl and aralkynyl. These are defined in more detail below.
In the definitions used in the present application, alkyl groups may be straight or branched chain groups and preferably have from 1 to about 12 carbon atoms, more preferably 1 to about 8 carbon atoms, still more preferably 1 to about 6 carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms. Methyl, ethyl and propyl including isopropyl are particularly preferred alkyl groups in the compounds of the present invention. As used herein, the term alkyl, unless otherwise modified, refers to both cyclic and noncyclic groups, although cyclic groups will comprise at least three carbon ring members.
Preferred alkenyl and alkynyl groups in the compounds of the present invention have one or more unsaturated linkages and from 2 to about 12 carbon atoms, more preferably 2 to about 8 carbon atoms, still more preferably 2 to about 6 carbon atoms, even more prefereably 2, 3 or 4 carbon atoms. The terms alkenyl and alkynyl as used herein refer to both cyclic and noncyclic groups, although straight or branched noncyclic groups are generally more preferred.
The aryl groups in the compounds of the present invention preferably have 6 to 10 carbon atoms in a single aromatic carbocyclic ring or in two or more fused rings. Phenyl and naphthyl groups, especially the phenyl group, are preferred.
The aryl groups may optionally be substituted on the aromatic ring by one or more substituents. When more than one substituent is present, the substituents may be the same or different. The number of substituents on the aryl group is restricted only by the number of substitutable positions and by steric constraints. However, we prefer that the aryl groups have from 1 to 5, more preferably 1 to 3, still more preferably 1 or 2, and most preferably only 1 substituent. The substituents may include hydrocarbyl, hydroxyl, hydrocarbyloxy, mercapto, hydrocarbylthio, hydrocarbylsulfinyl, hydrocarbylsulfonyl, nitro, amino, hydrocarbylamino, bis(hydrocarbyl)amino, hydrocarbylcarbonylamino, cyano, carbamoyl, hydrocarbylcarbamoyl, bis(hydrocarbyl)carbamoyl, carboxyl, hydrocarbyloxycarbonyl, formyl, hydrocarbylcarbonyl, hydrocarbylcarbonyloxy, optionally substituted heteroaryl or optionally substituted heterocyclic which are defined in more detail elsewhere in this specification.
Preferred aralkyl groups in the compounds of the present invention comprise an alkyl group having from 1 to 6 carbon atoms which is substituted with an aryl group as defined above to form an aralkyl group having a total of 7 to 16 carbon atoms. The aryl part of the aralkyl group may optionally be substituted on the aromatic ring by one or more substituents, the number and type of which is described above in relation to aryl groups. Examples of preferred aralkyl groups include benzyl, phenethyl, phenylpropyl, 1-naphthylmethyl and naphthylethyl, of which the benzyl group is most preferred.
Preferred aralkenyl and aralkynyl groups in the compounds of the present invention comprise an alkenyl or alkynyl group (preferably having 2 to 6 carbon atoms) which is substituted with an aryl group (as defined above) to form an aralkenyl or aralkynyl group having a total of 8 to 16 carbon atoms, Examples of preferred aralkyl groups include phenylethenyl (styryl) and phenylethynyl.
The hydrocarbyl groups in the compounds of the present invention may be substituted by a number of different groups, including hydrocarbyl, hydroxyl, hydrocarbyloxy, mercapto, hydrocarbylthio, hydrocarbylsulfinyl, hydrocarbylsulfonyl, nitro, amino, hydrocarbylamino, bis(hydrocarbyl)amino, hydrocarbylcarbonylamino, cyano, carbamoyl, hydrocarbylcarbamoyl, bis(hydrocarbyl)carbamoyl, carboxyl, hydrocarbyloxycarbonyl, formyl, hydrocarbylcarbonyl, hydrocarbylcarbonyloxy, optionally substituted heteroaryl or optionally substituted heterocyclic, which are defined in more detail elsewhere in this specification. The number of substituents on the hydrocarbyl group is restricted only by the number of substitutable positions and by steric constraints. However, we prefer that the hydrocarbyl groups have from 1 to 5, more preferably 1 to 3, still more preferably 1 or 2, and most preferably only 1 substituent.
The definitions given above for the various types of hydrocarbyl groups in the compounds of the present invention also apply to the hydrocarbyl part of the other possible groups in these compounds. These are defined in more detail below for the preferred case wherein the hydrocarbyl group is an alkyl group.
Preferred alkoxy groups in the compounds of the present invention include groups having one or more (but preferably only one) oxygen linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms, and most preferably 1, 2, 3 or 4 carbon atoms.
Preferred alkylthio groups in the compounds of the present invention have one or more (but preferably only one) thioether linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylthio groups having 1, 2, 3 or 4 carbon atoms are particularly preferred.
Preferred alkylsulfinyl groups in the compounds of the present invention include those groups having one or more sulfoxide (SO) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylsulfinyl groups having 1, 2, 3 or 4 carbon atoms are particularly preferred.
Preferred alkylsulfonyl groups in the compounds of the present invention include those groups having one or more sulfonyl (SO2) groups and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylsulfonyl groups having 1, 2, 3 or 4 carbon atoms are particularly preferred.
The halogen atoms in the compounds of the present invention are preferably fluorine, chlorine, bromine or iodine, of which chlorine and bromine are more preferred.
Preferred alkylcarbonyl (alkanoyl) groups in the compounds of the present invention include those groups having one or more carbonyl (CO) groups and from 1 to about 30 carbon atoms, more preferably from 1 to about 12 carbon atoms, and still more preferably 1 to about 6 carbon atoms (including the carbonyl carbon). Alkanoyl groups having 1, 2, 3 or 4 carbon atoms, especially the formyl, acetyl, propionyl, butyryl and isobutyryl groups, are preferred and the acetyl group is especially preferred.
The alkanoyl group may be substituted with one or more (but preferably only one) substituents, which may preferably be selected from halogen, hydroxy, alkoxy and cyano, especially a halogen atom, particularly chlorine or bromine.
Preferred alkylcarbonyloxy (alkanoyloxy) groups in the compounds of the present invention include those groups having one or more carbonyloxy groups and from 1 to about 30 carbon atoms, more preferably from 1 to about 12 carbon atoms, and still more preferably 1 to about 6 carbon atoms (including the carbonyl carbon). When the term xe2x80x9calkanoyloxyxe2x80x9d is used, it is to be understood that the group is attached to the rest of the molecule via the oxygen atom. Alkanoyloxy groups having 1, 2, 3 or 4 carbon atoms, especially the formyloxy, acetoxy, propionyloxy, butyryloxy and isobutyryloxy groups, are preferred and the formyloxy and acetyloxy groups especially preferred.
Preferred alkylcarbonylamino (alkanoylamino) groups in the compounds of the present invention include those-groups having an xe2x80x94NHxe2x80x94COxe2x80x94 linkage (the group being attached to the rest of the molecule via the nitrogen atom) and from 1 to about 30 carbon atoms, more preferably from 1 to about 12 carbon atoms, and still more preferably I to about 6 carbon atoms (including the carbonyl carbon). the group is attached to the rest of the molecule via the nitrogen atom. Alkanoylamino groups having 1, 2, 3 or 4 carbon atoms, especially the formylamino, acetylamino, propionylamino, butyrylamino and isobutyrylamino groups, are preferred and the formylamino and acetylamino groups especially preferred.
Preferred N-alkylcarbamoyl groups in the compounds of the present invention comprise a xe2x80x94COxe2x80x94NHxe2x80x94 linkage (the group being attached to the rest of the molecule via the carbonyl carbon) wherein the nitrogen atom is substituted with an alkyl group having from 1 to about 12 carbon atoms, more preferably 1 to about 6 carbon atoms. N-Alkylcarbamoyl groups having 1, 2, 3 or 4 carbon atoms, especially the N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl and N-butylcarbamoyl groups, are particularly preferred.
Preferred dialkylcarbamoyl groups in the compounds of the present invention comprise a xe2x80x94COxe2x80x94Nxe2x80x94 linkage (the group being attached to the rest of the molecule via the carbonyl carbon) wherein the nitrogen atom is substituted with two alkyl groups, each having from 1 to about 12 carbon atoms, more preferably 1 to about 6 carbon atoms. The alkyl groups may be the same or different. N,N-Dialkylcarbamoyl groups wherein each alkyl group has 1, 2, 3 or 4 carbon atoms, especially the N, N-dimethylcarbamoyl, N,N-diethylcarbamoyl, N-methyl-N-ethylcarbamoyl, N-ethyl-N-propylcarbamoyl, N,N-dipropylcarbamoyl, N,N-dibutylcarbamoyl and N-methyl-N-butylcarbamoyl groups, are particularly preferred.
Preferred monoalkylamino groups in the compounds of the present invention have one or more (but preferably only one) NH linkages and from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. Alkylamino groups having 1, 2, 3 or 4 carbon atoms, especially the methylamino, ethylamino, propylamino and butylamino groups, are particularly preferred.
Preferred dialkylamino groups in the compounds of the present invention have one or more (but preferably only one) nitrogen atom bonded to two alkyl groups, each of which may from 1 to about 12 carbon atoms, more preferably from 1 to about 8 carbon atoms, and still more preferably 1 to about 6 carbon atoms. The alkyl groups may be the same or different. Dialkylamino groups wherein each alkyl group has 1, 2, 3 or 4 carbon atoms, especially the dimethylamino, diethylamino, N-methylethylamino, N-ethylpropylamino, dipropylamino, dibutylamino and N-methylbutylamino groups, are particularly preferred.
Preferred alkoxycarbonyl groups in the compounds of the present invention include those groups having one or more (but preferably only one) oxycarbonyl groups and from 1 to about 30 carbon atoms, more preferably from 1 to about 12 carbon atoms, and still more preferably 1 to about 6 carbon atoms (including the carbonyl carbon). When the term xe2x80x9calkoxycarbonylxe2x80x9d is used, it is to be understood that the group is attached to the rest of the molecule via the carbonyl carbon. Alkoxycarbonyl groups having 1, 2, 3 or 4 carbon atoms, especially the methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and butoxycarbonyl are preferred and the methoxycarbonyl and ethoxycarbonyl groups especially preferred.
Heteroaromatic groups in the compounds of the present invention preferably have from 5 to 14 ring atoms in a single aromatic ring or in 2 or more fused rings. At least one of the ring atoms (preferably from 1 to 4 ring atoms, more preferably 1 to 3 ring atoms, even more preferably 1 or 2 ring atoms, and most preferably 1 ring atom) is a heteroatom, which is preferably selected from nitrogen, oxygen and sulfur atoms. The heteroaromatic group may optionally be fused to another heteroaromatic group or to an aryl group, examples of which are defined above. Examples of preferable heteroaromatic groups include pyridyl, furyl, thienyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, benzimidazolyl, benzofuryl, benzothienyl and benzisoxazolyl.
The heteroaromatic groups in the compounds of the present invention may be substituted by a number of different groups, including hydrocarbyl, hydroxyl, hydrocarbyloxy, mercapto, hydrocarbylthio, hydrocarbylsulfinyl, hydrocarbylsulfonyl, nitro, amino, hydrocarbylamino, bis(hydrocarbyl)amino, hydrocarbylcarbonylamino, cyano, carbamoyl, hydrocarbylcarbamoyl, bis(hydrocarbyl)carbamoyl, carboxyl, hydrocarbyloxycarbonyl, formyl, hydrocarbylcarbonyl, hydrocarbylcarbonyloxy, optionally substituted heteroaryl or optionally substituted heterocyclic, which are defined in more detail elsewhere in this specification. The number of substituents on the heteroaromatic group is restricted only by the number of substitutable positions and by steric constraints. However, we prefer that the heteroaromatic groups have from 1 to 5, more preferably 1 to 3, still more preferably 1 or 2, and most preferably only 1 substituent.
The heterocyclic groups (other than the heteroaromatic groups defined above) in the compounds of the present invention preferably contain from 3 to 14 ring atoms in a single ring or 2 or more fused rings. At least one of the ring atoms (preferably from 1 to 4 ring atoms, more preferably 1 to 3 ring atoms, even more preferably 1 or 2 ring atoms, and most preferably 1 ring atom) is a heteroatom, which is preferably selected from nitrogen, oxygen and sulfur atoms. The heterocyclic group may optionally be fused to a cycloalkyl group, a heterocyclic group, an aryl group or a heteroaromatic groups, examples of which are defined above. Preferred heterocyclic groups include azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, chromanyl and thiochromanyl.
The heterocyclic groups in the compounds of the present invention may be substituted by a number of different groups, including hydrocarbyl, hydroxyl, hydrocarbyloxy, mercapto, hydrocarbylthio, hydrocarbylsulfinyl, hydrocarbylsulfonyl, nitro, amino, hydrocarbylamino, bis(hydrocarbyl)amino, hydrocarbylcarbonylamino, cyano, carbamoyl, hydrocarbylcarbamoyl, bis(hydrocarbyl)carbamoyl, carboxyl, hydrocarbyloxycarbonyl, formyl, hydrocarbylcarbonyl, hydrocarbylcarbonyloxy, optionally substituted heteroaryl or optionally substituted heterocyclic, which are defined in more detail elsewhere in this specification. The number of substituents on the heterocyclic group is restricted only by the number of substitutable positions and by steric constraints. However, we prefer that the heterocyclic groups have from 1 to 5, more preferably 1 to 3, still more preferably 1 or 2, and most preferably only 1 substituent.
Preferably X is selected from xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CRxe2x80x94, xe2x80x94CRxe2x95x90CRxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, xe2x80x94CRxe2x95x90Nxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94NRxe2x80x94, and xe2x80x94Sxe2x80x94 (the group R representing C1-6 alkyl or C6-10 aryl).
More preferably, X is selected from xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90CRxe2x80x94, xe2x80x94CRxe2x95x90CRxe2x80x94, xe2x80x94Oxe2x80x94 and xe2x80x94Sxe2x80x94 (the group R representing C1-6 alkyl).
Most preferably, X is selected from xe2x80x94CHxe2x95x90CHxe2x80x94 and xe2x80x94Sxe2x80x94.
Preferably, one or two of Y1, Y2 and Y3 are halogen, and the other two or one are hydrogen.
More preferably, one of Y1, Y2 and Y3 is halogen, and the other two are hydrogen.
Most preferably, one of Y1, Y2 and Y3 is chlorine or bromine, and the other two are hydrogen.
Iodo is also a preferred possibility for one of the Y groups, with the other two being hydrogen.
Preferably, R1, R2 and R3 are independently selected from hydrogen, halogen, C1-6 alkyl (which may be optionally substituted with one or more substituents selected from halogen, hydroxy, C1-6 alkoxy and cyano), C6-10 aryl, optionally substituted C7-16 aralkyl, hydroxy, C1-6 alkoxy, C6-10 aryloxy, C7-16 aralkyloxy, C1-6 alkylthio, C6-10 arylthio, C7-16 aralkylthio, C1-6 alkylsulfinyl, C6-10 arylsulfinyl, C7-16 aralkylsulfinyl, C1-6 alkylsulfonyl, C6-10 arylsulfonyl, C7-16 aralkylsulfonyl, cyano, carboxyl, C1-6 alkyloxycarbonyl, C7-11 aryloxycarbonyl, C8-16 aralkyloxycarbonyl, heteroaryl and C1-30 aliphatic acyl (which may be optionally substituted with one or more substituents selected from halogen, hydroxy and C1-6 alkoxy and cyano)).
More preferably, R1, R2 and R3 are independently selected from hydrogen, halogen, C1-6 alkyl (which may be optionally substituted with one or more substituents selected from halogen, hydroxy and C1-6 alkoxy), C1-6 alkoxy, C6-10 aryl, heteroaryl, nitro, amino and C1-20 aliphatic acyl (which may be optionally substituted with one or more substituents selected from halogen, hydroxy and C1-6 alkoxy and cyano).
Still more preferably, R1, R2 and R3 are independently selected from hydrogen, halogen, C1-4 alkyl (which may be optionally substituted with one or more halogen atoms), C1-4 alkoxy, C6-10 aryl, heteroaryl, nitro, amino and C2-6 aliphatic acyl (which may be optionally substituted with one or more halogen atoms), provided that at least one of R1, R2 and R3 are other than hydrogen.
Yet more preferably, R1, R2 and R3 are independently selected from hydrogen, chlorine, bromine, methyl, ethyl, methoxy, ethoxy, acetyl, chloroacetyl, phenyl, morpholino, nitro, amino and bromoacetyl, provided that at least one of R1, R2 and R3 is other than hydrogen.
Even more preferably, R1, R2 and R3 are independently selected from hydrogen, chlorine, bromine, methyl, methoxy, phenyl, morpholino, nitro, amino and chloroacetyl, provided that at least one of R1, R2 and R3 is other than hydrogen.
As the person skilled in the art will readily appreciate, the preferred definitions of X, Y1, Y2, Y3, R1, R2, and R3 may be combined in various ways, and the compounds covered by all such combinations and permutations of the above preferred definitions are to be considered as being part of this invention. More especially, we prefer compounds wherein xe2x80x94Xxe2x80x94 is xe2x80x94Sxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94; is bromo-, dibromo-, chloro-, dichloro- or iodo- acetyl; R1 is one of the possibilities listed in Table 1 for R1, R2 or R3; R2 is one of the possibilities listed in Table 1 for R1, R2 or R3; and R3 is one of the possibilities listed in Table 1 for R1, R2 or R3.
Preferred compounds of formula (I) are selected from the following Table 1.
In further aspects, the present invention provides a pharmaceutical preparation, which contains as active ingredient a compound or compounds of the invention, as well as a process for its preparation.
Examples of pharmaceutical compositions include any solid (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) with suitable composition or oral, topical or parenteral administration, and they may contain the pure compound or in combination with any carrier or other pharmacologically active compounds. These compositions may need to be sterile when administered parenterally.
Synthesis of the Compounds of the Invention
Most of the compounds whose biological activity is the object of the present invention can be synthesised following a general procedure previously described [Conde, S.; Corral, C.; Madro{overscore (n)}ero, R.; Sxc3xa1nchez Alvarez-Insxc3xaa, A.; Fernxc3xa1ndez-Tomxc3xa9 M. P.; del Rxc3xado. J.; J. Med. Chem. 1977, 20, 970-974]. Following this synthetic method, an aromatic or heteroaromatic compound of formula II reacts with a mixture of a substituted acetyl halide of formula III, e. g. chloroacetyl chloride, bromoacetyl bromide, etc, and a Lewis acids, such as TiCl4, SnCl4, AlCl3, etc, in an aprotic anhydrous organic solvent, for example, CS2, CCl4, etc. This process is represented in Scheme 1, where Yxe2x80x2 represents a halogen atom (F, Cl, Br or I). 
Another group of compounds can be synthesised by the general synthetic procedure of halogenation [described, for example, in: Seeger, D. E.; Lahti, P. M.; Rossi, A. R.; Benson, J. A.; J. Am. Chem. Soc. 1986, 108, 1251-1265] represented in Scheme 2. Following this procedure, an aromatic or heteroaromatic ketone IV is treated with the desired halogen in the medium of a polar organic solvent, such as acetic acid, dioxane, etc, to obtain the xcex1-halomethyl ketone V, which falls within the scope of compounds of formula I but has a single halogen atom Y. 
Activity of the Compounds of the Invention
In the following examples, the selective enzyme GSK-3 inhibition by the compounds of the invention is demonstrated. As described above, it has been established that the enzyme GSK-3 plays a crucial role in the ethiopathogenia of AD as responsible of the hyperphosphorylation of the protein tau observed in this pathology. Because of the biological activity of these products as GSK-3 inhibitors, they can be considered as important prototypes or lead compounds of a new family of compounds that can prevent the formation of neurofibrillary tangles and reverse those already formed.
The compounds of the invention are capable of inhibiting the enzyme GSK-3. The compounds of the invention are therefore useful as therapeutical agents in the treatment of neurodegenerative diseases, such as AD or any other associated to the pathology of protein tau, or to the activation of GSK-3, such as non-insulin dependent diabetes mellitus.
In addition, due to their ability to inhibit the cellular cycle, the compounds of the invention are also useful in the treatment of hyperproliferative diseases, for example, displasias and metaplasias of different tissues, psoriasis, arteriosclerosis and cancer. Their application in the treatment of these pathologies forms also part of the present invention.
WO 9640982 provides compositions for therapy of neurodegenerative disease comprising an efficacious amount of a selective PLA2 inhibitor. p-Bromophenacyl bromide is given as an example of such a selective PLA2 inhibitor. The present invention disclaims this use of p-bromophenacyl bromide. In preferred compounds of this invention, a phenacyl bromide is not subsituted with one substituent which is p-bromo, or a p-bromoacetophenone compound does not have one subsituent which is xcex1-bromo, or the compound is not a selective PLA2 inhibitor.